JP2003518492A - Combination of opioid analgesic and trimebutine - Google Patents

Abstract

The invention provides a combination of of trimebutine Ä2-dimethylamino-2-phenylbutyl-3, 4, 5- trimethoxy-benzoate hydrogen maleateÜ or its corresponding stereoisomers with an opioid analgesic for the preparation of a medicament to prevent and/or treat pain or nociception.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The field of the invention relates to methods of preventing and / or treating pain. More specifically,
The present invention relates to trimebutine (tr) for the prevention and / or treatment of pain and nociception.
imebutine) [2-dimethylamino-2-phenylbutyl-3,4,5
-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomer and an opioid analgesic combination.

BACKGROUND OF THE INVENTION Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate; TMB] has been the irritable bowel syndrome (IBS) in many countries since 1969. Have been used to treat functional bowel disorders, including The efficacy of this compound in reducing abdominal pain has been demonstrated in various clinical trials using various treatment methods (Luttece, 1980; Moshal.
and Herron, 1979, Toussaint et al., 1981; Ghid.
ini et al., 1986). Trimebutin is found in rat brain and guinea pig (Roman).
Et al., 1987) or the feline (Allescher et al., 1991) intestinal opioid receptor and was found to exhibit weak agonist activity without selectivity for any of the μ-, δ- and κ-subtypes. ing.

This weak activity has been confirmed when isolated intestinal fragments are used under transmural stimulation (Pascand et al., 1987). This property may be responsible for the regulatory effect of trimebutine on gut motility in fasted dogs. Trimebutin, administered by the iv route or orally, is associated with the locomotor complex (m)
Phase III of the lighting motor complex (MMC)
Delayed the appearance of (Bueno et al., 1987). In humans, trimebutine stimulates intestinal motility in both fed and fasted states (Grandjoua).
n et al., 1989). Furthermore, trimebutin reverses the stress effects of jejunal motility (Delis et al., 1994).

More recently, it has been demonstrated that trimebutine can influence the activity of visceral affairs by reducing the rectal-colon reflex intensity in the rat. This was evidenced by inhibition of colonic motility following rectal dilation (Julia et al., 1996). This result may be related to the beneficial effects found with trimebutine in patients with IBS and more specifically in the treatment of abdominal pain attacks. Pain is defined as a sensory experience that is accepted by neural tissue that is distinguished from sensations such as touch, pressure, heat or cold. The precise definition of pain is difficult due to its widespread perception and the varying acceptance of pain by different individuals, but can be divided into three categories: acute pain, inflammatory pain. And chronic pain.

Generally speaking, physicians and patients expect more effective and safe compounds for the treatment and / or prevention of pain. It is especially true for chronic pain, where it is generally accepted that there is an unmet medical need for the treatment (9th World Congres).
Son Pain, Vienna, August 1999). NSAID and opiate formulations are often nearly ineffective. Antidepressants are used with varying effects (50-60%). Some anticonvulsant drugs [carbamazepine (carb
amazepine), clonazepam, baclofen] may be active. In extreme cases, capsaicin and local anesthetics have been tried. However, none of these measures are satisfactory, and some patients are unresponsive to all of these. In some cases, such as trigeminal neuralgia, neurosurgery [differential thermal coagulation of Gasser ganglia] remains the only method of pain relief.

[0006] In this regard, clinical trials and animal studies have examined opiate formulations and bupivacaine (bupi).
Vaccine) has been shown to improve the extent and duration of pain relief when compared to each of these medications administered separately (Meert and Melis, 1992). Furthermore, NMDA (N-methyl-D-aspartate) type glutamate receptors are considered to play an important role in the transmission of excitation signals from primary sensory neurons that reach the brain via the spinal cord (Dickenson et al. 199
0), a strategy has been devised for the treatment of pain by the combined administration of NMDA antagonists and opioid analgesics (WO99 / 44610). Unfortunately, some formulations such as dextromethorphan have been reported to induce unacceptable side effects.

From the origin of visceral pain, the inventor has demonstrated that trimebutine has an inhibitory effect on glutamate release by blocking sodium channels, as demonstrated herein, and compared to lidocaine 17 It has been found that it can act as a local anesthetic with twice the potency. Surprisingly, the inventor found that non-NM
When a DA receptor antagonist trimebutine or its derivative is administered in combination with an opioid analgesic, it has an opioid analgesic effect on the one hand and an inhibitory effect on pain, and on the other hand, drug dependence and constipation It has been found to reduce the undesired side effects of the opioid analgesics that include. No general teaching suggesting the combination of opioid analgesics with trimebutine or its stereoisomers is found in the prior art.

[0008] According to these results, it was demonstrated that trimebutine can have effects on pain states other than visceral pain, and that trimebutine is useful for the treatment and / or prevention of pain.

SUMMARY OF THE INVENTION The present invention provides trimebutine [2-dimethylamino-2-phenylbutyl-3,4
, 5-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomer and an opioid analgesic. The components of the product can be used as a combined preparation, simultaneously, separately or sequentially, for the treatment and / or prevention of pain and / or nociception. The present invention also relates to trimebutine [2-dimethylamino] as a combined preparation for use for the treatment or prevention of pain, or for anesthesia, simultaneously, separately, sequentially or over a period of time. 2-Phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of their metabolites, or at least one of their corresponding stereoisomers and opioid analgesia A product containing a drug.

In the context of the present invention, the term pain refers to nociception, hyperalgesia, allodynia, pain associated with hypersensitivity, somatic pain, visceral pain, acute pain, chronic pain, post-operative pain. It may mean pain, headache, inflammatory pain, neurological pain, muscle-skeletal pain, cancer-related pain or vascular system pain. From the viewpoint of the present invention, the term anesthetic may mean a local or general anesthetic, preferably a local anesthetic.

In this regard, the opioid analgesic is preferably morphine, but also codeine, dihydrocodeine, diacetylmorphine, hydrocodone.
done), hydromorphone, levorphanol, onyxmorphone
), Alfentanyl, buprenorphine (bupr)
enorphine), butorphanol, fentanyl, sulfentanyl,
Meperidine, methadone, nalbuphine, propoxyphene
ne) and pentazocine or their acceptable salts.

The present invention also provides a pharmaceutical composition containing trimebutine or its corresponding stereoisomer and an opioid analgesic together with at least one pharmaceutical carrier or excipient. The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic, at least one pharmaceutical agent. Pharmaceutical compositions, aggregates, associations or mixtures are provided for inclusion with carriers or excipients.

Another aspect of the invention relates to the use of trimebutine or its corresponding stereoisomer and an opioid analgesic for the preparation of a medicament, said medicament being used for the treatment of pain and / or nociception and / or Or, it contains both trimebutine and an opioid analgesic in a single dosage form that can be used simultaneously in prophylaxis, separately, or sequentially, or as a separate dosage form. In this regard, the present invention is useful in the prevention and / or treatment of acute pain, inflammatory pain and / or chronic pain.

Another aspect of the invention is trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of those. The use of metabolites or at least one of their corresponding stereoisomers and opioid analgesics as a medicament. Another aspect of the invention is trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or At least one of their corresponding stereoisomers and opioid analgesics is for use in the treatment or prevention of pain.

Another aspect of the invention is trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of those. The use of metabolites or at least one of their corresponding stereoisomers in combination with opioid analgesics consists in reducing the dose of said opioid analgesics. Another aspect of the invention is trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or The use of at least one of their corresponding stereoisomers in combination with an opioid analgesic is to reduce the side effects or disadvantages of at least one of the opioid analgesics.

In view of the present invention, the side effects or disadvantages can be sedation, hypopnea, suppressed gastrointestinal motility, constipation, nausea, tolerance, addiction, toxicity or vomiting. From the viewpoint of the present invention, trimebutine is 50 to 900 mg / day, preferably 30.
The opioid analgesic is administered at a dose of 0-600 mg / day, and the opioid analgesic is administered at a dose of 0.01-250 mg / day, depending on the opioid analgesic selected. Preferably, the opioid analgesic is morphine, which is administered at a dose of 2-220 mg / day. The present application also relates to a method of treating and / or preventing pain and / or nociception, which method comprises administering to a patient in need thereof trimebutine and an opioid analgesic. The administration of the trimebutine and opioid analgesic can be administered simultaneously, separately or sequentially.

The present application also relates to a method of preventing and / or treating pain, which method provides patients in need thereof with trimebutine [2-dimethylamino-2-phenylbutyl-
3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyltrimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic. To do. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], at least one of their metabolites or at least one of their corresponding stereoisomers and opioid analgesics is Administration can be simultaneous, separate or sequential.

The present invention also relates to a method for producing a pharmaceutical composition containing trimebutine or a stereoisomer thereof and an opioid analgesic, the method comprising: Including compounding. The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic Regarding the manufacturing method,
This method is based on trimebutine [2-dimethylamino-2-phenylbutyl-3,4,4].
5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic, a pharmaceutically acceptable carrier or Including with an excipient.

DESCRIPTION OF THE FIGURES FIG. 1: [ ³ H] -batracotoxin (b bound to rat cortical synaptosomes.
Effect of TMB (A), Nor-TMB (B) and their corresponding stereoisomers on atrachotoxin). Membranes are incubated with increasing concentrations of test drug in the presence of 25 μg scorpion venom and 10 nM [ ³ H] -batracotoxin. Non-specific binding was determined as 0.
It is measured in the presence of 3 mM veratridine. After 90 minutes incubation at 20 ° C., bound ligand is separated from free ligand by vacuum filtration through a GF / B filter. Specific binding in the presence of test compound is calculated as the percentage of control binding measured in the absence of inhibitor. Numerical values shown are the mean ± SEM from at least 3 independent measurements made in duplicate.

FIG. 2: Effect of TMB (A), Nor-TMB (B) and their corresponding stereoisomers on veratridine-induced glutamate release from rat spinal cord slices. Morphine and bupivacaine (C) are tested under the same conditions. Results are mean ± SD of at least 10 measurements. E. M. Is. These slices were thawed with the test compound for 15 minutes and then veratridine (4
0 μM). By measuring the radioactivity taken every 5 minutes for 30 minutes after stimulation and comparing the effect of the compound with the amount of accumulated radioactivity released relative to the amount obtained in cells superfused with buffer alone. decide. ^* P <0.05; ^**
P <0.01; ^*** P, 0.001, Student's test.

FIG. 3: Effect of TMB on sodium current measured in DRG neurons. (A) Body Na ⁺ current evoked every 10 seconds by shifting the membrane potential from −80 mV to −10 mV. TMB is 0.1 μM (bottom row) and 1 μM for 20 seconds
Apply locally in (top row). (B) Sodium current before TMB injection (control) and after injection (same cell as A). (C) Peak sodium current vs. pulse potential in control saline and in the presence of the indicated concentration of TMB. A similar decrease in peak sodium current occurred. (D) Dose-response relationship of TMB effect on DRG Na ⁺ . Results are expressed as the Na ⁺ current fraction (relative peak Na ⁺ current) persisting in the presence of the blocker. Each point is the average value ± S.D. Of 4 to 6 tests. E. M. Is.
Continuous curve: Hill with IC ₅₀ = 0.69 μM and n _H = 1.02.
Best fit to the function.

FIG. 4: Local anesthetic effect of TMB (A) and lidocaine (B) measured on rabbit corneal reflex. Numbers are the median percent inhibition of corneal reflexes calculated for each set of 10 stimuli. The x-axis represents the elapsed time (minutes) after instillation. ^* P <0.05; ^** P <0.01 [Mann-Whitney (compared to vehicle-treated controls)
Mann-Whitney U test].

FIG. 5: Percentage of analgesic activity before and after treatment in 5 different groups of animals, designated native, control, T1, T2 and T3, respectively, in the graphs of this figure. Calculated according to c) of Example 5. "Natural" in this graph
The group referred to as is first given saline and then treated with vehicle without morphine or trimebutine. The group referred to as the "control" in this graph is first given PGE2 and then treated with vehicle without morphine or trimebutine. The group designated T1 in this graph is first given PGE2 and then treated with 0.3 mg / kg morphine. The group designated T2 in this graph is first given PGE2 and then treated with trimebutine 100 mg / kg. The group designated T3 in this graph is first given PGE2 and then treated with morphine 0.3 mg / kg and trimebutine 100 mg / kg.

FIG. 6: Percentage of analgesic activity before and after treatment is shown in the graph of this figure as
Calculated according to example 5c) in 6 different groups of animals designated as native, control, Ml, M2, M3 and M4. The group referred to as "natural" in this graph was given saline first, then without morphine or trimebutine,
Treated with vehicle. The group referred to as the "control" in this graph is first given PGE2 and then treated with vehicle without morphine or trimebutine. The group designated M1 in this graph was initially PGE2
And then treated with morphine 0.3 mg / kg. M2 in this graph
The group referred to as is given PGE2 first, then morphine 1 mg / kg
Will be treated. The group designated M3 in this graph is first given PGE2 and then treated with morphine 3 mg / kg. The group designated M4 in this graph is first given PGE2 and then treated with morphine 6 mg / kg.

DETAILED DESCRIPTION OF THE INVENTION After it was identified that trimebutine can inhibit glutamate release involved in the transmission of nociceptive stimuli by blockade of sodium channels, the present inventors have shown that trimebutine is a member of lidocaine. It has been shown that it can act as a local anesthetic with an ability that is surprisingly substantially greater than its ability. The present inventors have also determined that the combined administration of trimebutine or its stereoisomer and an opioid analgesic has a potent synergistic effect in the treatment and / or prevention of pain.

Accordingly, the present invention provides trimebutine [2] as a combination formulation for the treatment and / or prevention of pain, simultaneously, separately, sequentially or over an extended period of time, or for anesthesia.
-Dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and It relates to products containing opioid analgesics. From the perspective of the present invention, the term anesthesia may mean local or general anesthesia, preferably local anesthesia.

In this regard, the present invention provides, at all times, to respond or meet the need for pain relief with more effective and safe compounds, trimebutine [2-dimethylamino-2-phenylbutyl-3, 4,5-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomer and an opioid analgesic. In this regard, the components of the product may be simultaneously, separately or sequentially.
It can be used for the treatment and / or prevention of pain and / or nociception. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate, TMB] has been shown to be active in reducing abdominal pain in humans.

Furthermore, it is known that in humans, after oral or intravenous (iv) administration of trimebutine, trimebutin acts as a metabolic precursor of N-desmethyl trimebutine (Nor-TMB). This means that trimebutine is Nor-TMB.
It means that it acts in the same manner as the biological precursor of, and that the biological precursor trimebutin is metabolized under the action of the liver enzyme to produce a new molecule. It is certain that administration of trimebutine in humans leads to concomitant exposure of trimebutine, Nor-TMB and other metabolites. Thus, these compounds, especially trimebutine and Nor-TMB, can elicit their (antinociceptive) properties together.

Therefore, N-desmethyl trimebutine (Nor-TMB) is a stereoisomer (S
) N-desmethyl trimebutine and (R) N-desmethyl trimebutine and the corresponding racemates. Opioid analgesics are well established as a class of analgesics. Sometimes these are also referred to as opiates, but the term should be preserved for morphine-related chemicals. It is generally accepted that the term opioid is intended in a generic sense to refer to any drug, natural or synthetic, that has a morphine-like effect.

Synthetic or semi-synthetic opioid analgesics are derivatives of five chemical compounds: phenanthrenes, phenylheptylamines, phenylpiperidines, morphinans and benzomorphans. In terms of the present invention, opioid analgesics include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol.
anol, onyxmorphone, alfentanyl, buprenorphine
), Butorphanol, fentanyl
nyl), sulfentanyl, meperidine (mep)
eridine), methadone, nalbuphine (nalb)
upine), propoxyphene and pentazocine or their acceptable salts. Preferably the opioid analgesic is morphine or an acceptable salt thereof.

Of all opioid analgesics, morphine is the most widely used and in this respect is the archetypal compound. Unfortunately, apart from its useful therapeutic properties, morphine also has many disadvantages, including sedation, respiratory depression, decreased gastrointestinal motility (which causes constipation), and in some individuals nausea. And vomiting may occur. Another disadvantage, which has always been reported, is the development of resistance and physical dependence, which limit the symptomatic use of such compounds. Therefore, allowing opioid analgesics such as morphine to be used by physicians in low doses, thereby reducing the potential for adverse effects, including development of tolerance and dependence, and thus two major problems. There is a need for a way of avoiding the need for increased or increased doses in the case of long-term treatments leading to the development of side effects and the risk of drug dependence associated with discontinuation of administration.

The present invention relates to trimebutine [2-dimethylamino-2-phenylbutyl-3,4
, 5-Trimethoxy-benzoate hydrogen maleate], N-desmethyltrimebutine, at least one of their metabolites or at least one of their corresponding stereoisomers and opioid analgesics We first showed the particular importance of having a common effect. This new type of combination has the following important and unexpected properties: -reduction or suppression of the adverse effects of opioid analgesics, and / or

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one of them. Of the effect or potency of the corresponding stereoisomers of O., with opioid analgesics and vice versa, and / or -The synergism that occurs between desmethyl trimebutine, at least one of their metabolites or at least one of their corresponding stereoisomers and an opioid analgesic.

Accordingly, the present invention relates to trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of their metabolites or It relates to the use of at least one of their corresponding stereoisomers in combination with an opioid analgesic to reduce the dose of said opioid analgesic. Trimebutin [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one in combination with an opioid analgesic Their corresponding stereoisomers of the species are
Administration can be simultaneous, separate or sequential.

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyltrimebutine, at least one metabolite thereof or at least one of them. The combination of the corresponding stereoisomer with an opioid analgesic dramatically reduced the opioid analgesic dose compared to the amount of opioid analgesic required without the combination of opioid analgesics. It is possible to let. The use of reduced doses of opioid analgesics, in particular, makes it possible to reduce or suppress the side effects of opioid analgesics.

Therefore, trimebutine [2-dimethylamino-2-phenylbutyl-3,4,4]
5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of their metabolites or at least one of their corresponding stereoisomers, the opioid analgesic dose is , Compared to the dose of opioid analgesic required without the combination of opioid analgesics,
It can be reduced by 10 to 99%. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof. The combination of isomers and opioid analgesics can increase the efficacy of opioid analgesics in the treatment of pain. This potency can be increased at least 3-fold.

Opioid analgesics and trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one The combination of the species with their corresponding stereoisomers has led to the use of trimebutine [2-
Dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof Can be increased. This potency can be increased at least 3-fold.

The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyltrimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof in combination with an opioid analgesic, It relates to reducing at least one side effect or disadvantage of the opioid analgesics. From the viewpoint of the present invention, the side effects or disadvantages can be toxicity, tolerance, physical dependence, sedation, respiratory depression, decreased gastrointestinal motility, nausea or vomiting.

The present invention relates to trimebutine [2-dimethylamino-2-phenylbutyl-3,4
, 5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one of their metabolites or at least one of their corresponding stereoisomers and opioid analgesics. The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic for the treatment or prevention of pain. Regarding to use.

The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomers and opioid analgesics are advantageously used for the prevention and / or treatment of pain and / or nociception. Thus, the compounds of this combination formulation may be used for the treatment and / or prevention of pain and / or nociception, simultaneously, separately or sequentially. The term "pain" includes all types of pain of all causes. More specifically, the present invention is useful in the prevention and / or treatment of acute pain and any inflammatory pain (abdominal or stomach), and chronic pain.

Interestingly, we have found that trimebutine and Nor in the following description.
-Its metabolite called TMB (preferably the (S) -enantiomer), which is one of its major metabolites in humans, inhibits glutamate release from rat spinal cord slices by blocking sodium channels. Confirmed to do.
In particular, trimebutine, its stereoisomer, and Nor-TMB have their affinity for sodium channels labeled with [ ³ H] -batracotoxin, their effect on sodium currents in rat dorsal root ganglion neurons, rat spinal cord. They were tested for their effect on veratridine-induced glutamate release from slices.

These results are of particular interest as the critical roles of glutamate and excitotoxic amino acids (EAA) in establishing hyperalgesia or allodynia have been demonstrated by Dickenson et al. (1995). From that discovery, a strategy was initiated to discover new analgesics based on inhibition of glutamate and EAA receptors. Most of the inhibitors found from these strategies cannot be used in humans because of safety concerns, and thus blockade of glutamate receptors is currently considered a difficult tool for drug discovery. Be done.

Furthermore, the results reported in the examples show that trimebutine, its stereoisomers and its metabolites show analgesic activity and also an inhibitory effect on pain, in particular inflammatory and chronic pain. Has proved. In the context of the present invention, the term pain refers to nociception, hyperalgesia, allodynia, pain associated with hypersensitivity, somatic pain, visceral pain, acute pain, chronic pain, postoperative pain, headache. , Inflammatory pain, neurological pain, musculoskeletal pain, cancer-related pain or vascular system pain. Examples of acute pain include post-operative pain and headache, among others.

Inflammatory pain is an inflammatory condition such as arthritis, polyarthritis, spondyloarthritis, musculoskeletal pain such as bone traumatic pain, and phantom limb pain, back pain, vertebral pain, ship-shaped disc operation failure (shipped). disc surgery failure), post-operative pain, rheumatic pain, toothache and dysmenorrhea. International Conference on Pain Research
according to the definition proposed by the ation for the Study of Pain, chronic pain is pain that persists beyond the recovery period of normal tissues (3 months is suggested) (international conference on pain research. , Chronic Pain Classification, Pain, 1986, Suppl. 3, S1-S226), which also represents a transition point from acute pain.

Chronic pain results from hyperalgesia (Dickenson et al., 1995.
), The invention also encompasses the prevention and / or treatment of pain associated with hyperalgesia or central hypersensitivity conditions. Examples of chronic pain include neurological pain, eg, neuropathies, polyneuropathy including those associated with diabetes, headache, trauma, neuralgia including postherpetic neuralgia and trigeminal neuralgia, pain dystrophies, HIV-related Pain, cancer-related pain, vascular pain such as those resulting from Raymond syndrome, Houghton's disease, arteritis, varicose ulcers are included.

From the viewpoint of the present invention, trimebutine is 50 to 900 mg / day, preferably 30.
It is administered at a dose of 0-600 mg / day (male with an average body weight of 70 kg). The opioid analgesic is administered at a dose level up to the conventional dose level for that analgesic, but is preferably administered at reduced levels according to the present invention. Suitable dose levels will depend on the analgesic effect of the opioid analgesic chosen, but typically suitable dose levels will be from about 0.001 to 25 mg / kg / day, preferably 0.
005-10 mg / kg / day, especially 0.005-5 mg / kg / day or 0.01-250 mg / day depending on the opioid analgesic selected (70 kg
Men with an average weight of.

The compound may be administered up to 6 times a day, preferably 1 to 4 times a day. As an example, the dose is preferably 2-220 mg / day for morphine, 20-60 mg / day for codeine, 0.1-1 mg / 24 for fentanyl.
Time can be 2-10 mg / day for droperidol and 20-80 mg every 4 hours for oxycodone (male with an average weight of 70 kg).

When administered as a combination therapy or in combination as a single or separate pharmaceutical composition, trimebutine or a stereoisomer thereof and the opioid analgesic are present in proportions consistent with the onset of the desired effect. In particular, a weight ratio of trimebutine to opioid analgesic is suitably about 1 to 1. Preferably, this ratio is 0.0001 to 1-10.
It is 00 to 1, especially 0.01 to 1 to 100: 1. In another aspect of the invention, there is provided a pharmaceutical composition comprising trimebutine or its corresponding stereoisomer and an opioid analgesic.

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one of those. There is provided a pharmaceutical composition, aggregate, association, or mixture containing the corresponding stereoisomer and opioid analgesic together with at least one pharmaceutical carrier or excipient. From this point of view, trimebutine present in a pharmaceutical composition in combination with an opioid analgesic is useful in the prevention and / or treatment of the above types of pain. The pharmaceutical composition is
Containing trimebutine and / or its corresponding stereoisomers, including their salts, and formulating this active compound into dosage units with at least one solid or liquid pharmaceutically acceptable carrier or excipient. Manufactured by

When it is desired to form a salt, pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, ditartrate, calcium acetate, camsylate, carbonate, citrate, Edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoloylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloric acid, hydrogen carbonate, hydroxynaphthoate , Iodide, isethionate, lactate, lactobionate, malate, maleate, mandephosphate, mesylate, methylnitrate, methylsulfate, mucate, napsylate, nitrate, palmoate (embonate), pantothenate, phosphate / Diphosphate, polygalacturonate , Salicylate, stearate, subacetate, succinate or hemi-succinate, sulfate or hemi-sulfate, tannate, tartrate or hemi-tartrate, theocrate, triethiozide, benzathine, chloroprocaine, Choline,
Includes diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium, and aene (Berge SM;
"Pharmaceutical salt," J. et al. Pharm. Sci. 66: 1-19 (1997)
, Which is incorporated herein by reference.

Salts of opioid analgesics are also prepared according to known methods, suitable salts for the oral or parenteral route. Suitable solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is at least one inert, conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or spreader. , For example starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) wetting agents such as glycerol, ( d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates,
And sodium carbonate, (e) solution retarders such as paraffin, (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, and glycerol monostearate, (h) adsorbents such as Mixing with kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or mixtures thereof. In the case of capsules, tablets and pills, these dosage forms can also contain buffering agents.

Solid compositions with similar morphology can also be used as fillers in soft or hard filled gelatin capsules, in which case excipients such as lactose and high molecular weight polyethylene glycols are used. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings or shells such as enteric coatings and coatings or shells known in the art. If desired, the active ingredient can also be in micro-encapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. These liquid dosage forms include, in addition to trimebutine and / or opioid analgesics, inert diluents conventional in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , Ethyl acetate, benzyl alcohol and the like. Suspensions include, in addition to trimebutine and / or opioid analgesics, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydrooxide, bentonite, agar and tragacanth gum, Alternatively, it may contain a mixture of these substances.

Compositions suitable for parenteral injection are for reconstitution into sterile physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injectable solutions or dispersions. Sterile powder can be included. Examples of suitable liquid carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), and suitable mixtures thereof. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol and sorbic acid. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.

Preferably the composition is in unit dosage form. In such form, the formulations are subdivided into unit dosage forms containing appropriate quantities of trimebutine and / or opioid analgesics. Such unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. it can. The unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form. Some examples of unit dosage forms include tablets, capsules, pills, powders, suppositories, aqueous and non-aqueous oral solutions and suspensions, which are packaged in containers that can be divided for each administration. , And parenteral solutions.

The route of administration is preferably the oral or parenteral route, especially by injection, including the intravenous and subcutaneous injection routes. However, whichever route fits,
Intradermal, intramuscular, intrathecal, intraperitoneal routes, for example, may also be considered in the context of the present invention. The present application also relates to a method of preventing and / or treating pain, which method comprises trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, Administering at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic to a patient in need thereof. Trimebutin [2-
Dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], at least one of their metabolites or at least one of their corresponding stereoisomers and opioid analgesics are administered simultaneously. , Can be administered separately or sequentially.

Another aspect of the invention relates to a method of preventing and / or treating pain and / or nociception, which method comprises administering trimebutine and an opioid analgesic to a patient in need thereof. . In view of the present invention, the administration of these two compounds can be simultaneous, separate or sequential. The term "patient" is intended to include all animals, especially humans, to whom trimebutine and opioid analgesics are administered.

The present invention also relates to trimebutine [2-dimethylamino-2-phenylbutyl-3
, 4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic Regarding the manufacturing method,
This method is based on trimebutine [2-dimethylamino-2-phenylbutyl-3,4,4].
5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic, a pharmaceutically acceptable carrier or Including with an excipient.

Another aspect of the present invention provides a method of preparing a pharmaceutical composition containing trimebutine or a stereoisomer thereof and an opioid analgesic, which method is acceptable for the use of trimebutine and an opioid analgesic. Formulation with a carrier or excipient. The biochemical and pharmacological data reported in the examples allow a better understanding of the mechanism of action of trimebutine when combined with opioid analgesics. These data have been previously reported and, in addition to the regulatory effect on colonic motility associated with its weak opioid-like properties, trimebutine has a Na ⁺
It supports the hypothesis that its blocking action on channels confers antinociceptive properties. These new properties of TMB explain how this compound, when combined with opioid analgesics, is a useful method for the prevention and / or treatment of pain.

The invention will be further described by the following examples. These examples do not limit the scope of the invention. Examples Materials and Methods Animals In this study, male Sprague-Dawley rats (IFFA Credo, weighing 225 to 250 g ([ ³ H] -batracotoxin binding test) or 350 to 375 g (glutamate release test) were tested. Sain
t Germain sur l'Arbresle, France) or pregnant rats (electrophysiological test) and are bred according to institutional guidelines for animal welfare: temperature 21 ± 3 ° C; light / dark: 12 hours / 12 hours.

Drugs and Vehicles Trimebutin maleate, (S) -trimebutine, (R) -trimebutine are
French Patent FR2,369M (1962) and Japanese Patent Application Publication No. 1
Synthesized according to the method described in 6416 (1980). These publications are incorporated herein by reference. Flunarizine, L-glutamic acid, lidocaine hydrochloride, bupivacaine, trypsin and DMEM-F12 are sigma (Sigma).
) (St. Quentin Fallavier, France),
Morphine is from Francopia (Gentilly, Franc)
CE) and veratridine is RBI, Bioblock Scientific (Bioblock Scientific) (
Illkirch, France) and purchase gentamicin (gentam)
icine is Boehringer Mannhe
im S. A). (Meylan, France). All reagents used in the preparation of buffers and solutions were Merck (Merck-Cl).
Evenot, Nogent sur Marne, France).

(S) -N-desmethyl-TMB maleate is synthesized according to the method described in WO99 / 01417. This publication is incorporated herein by reference. L- [G- ³ H] - glutamic acid (49Ci / mmol) is Amersham (
Amersham) (Les Ulis, France). Dulbecco's Modified Eagle Medium, Neurobasal (Ne
urobasal) medium, fetal bovine serum, Gibco Life Technology SARL
(Gibco, Life Technologies SARL). (C
(Ergy Pontoise, France). Horse serum is from Seromed (Berlin, Germany).

Example 1 [ ³ H] -Batrachotoxin Binding The purpose of this example was to test compound affinity for the [ ³ H] -Batrachotoxin binding site in rat cortical synaptosomes, representing site 2 of the sodium channel. Is to measure. 1.1 Materials and Methods a) Synaptosomal Membrane Brain cortex from male Sprague-Dawley rats was ice-cold 0.32 in a glass-Teflon® homogenizer.
Homogenize in 10 volumes of M sucrose, 5 mM K ₂ HPO ₄ (pH 7.4 at 4 ° C.). The homogenate is centrifuged at 1000 g for 10 minutes; the new pellet is resuspended in the same volume of sucrose and then recentrifuged. The new pellet is discarded and the two supernatants resulting from these two centrifugations are collected and then centrifuged at 20,000g for 10 minutes. Generate 50 pellets
mM HEPES (N-2-hydroxyethylpiperidine-N′-2-ethanesulfonic acid), 5.4 mM KCl, 0.8 mM MgSO ₄ , 5.5 mM glucose and 130 mM choline chloride containing sodium free assay. Resuspend in working buffer (pH 7.4 at 25 ° C).

B) Binding Assay The binding assay is based on the scorpion venom (Leireus quinquestriatu).
s) by adding 150-200 μg of synaptosome protein to assay buffer (250 μl final volume) containing 25 μg, 0.1% BSA, 10 nM [ ³ H] -batracotoxin and various concentrations of test compound. , Started. Non-specific binding is measured in the presence of 0.3 mM veratridine. The reaction mixture was incubated at 25 ° C. for 90 minutes, then GF / B filter (Fi
Bound ligand was separated from free ligand by vacuum filtration through a latterate, Packard). Filter this filter with 2 x 5 ml buffer (5 mM
Wash with HEPES, 1.8 mM CaCl ₂ , 0.8 mM MgSO ₄ , 130 mM choline chloride, 0.01% BSA; pH 7.4 at 25 ° C., then liquid scintillation spectrophotometer (Topcount, Packard).
) Is used to assess the bound ligand.

C) Calculations In all of the studies evaluating displacement of [ ³ H] -batracotoxin binding by unlabeled drug, concentration-response curves are generated using 6 drug concentrations. All assays are done at least 3 times; each measurement is done in duplicate. Data are expressed as the mean ± SEM of at least 3 measurements. The displacement curve was fitted by Graph-Pad Software. The permutation plot is the LIGAND computer program (Mc
Non-linear regression analysis using Pherson (1985). These analytical values yield the Hill coefficient (n _H ) and IC ₅₀ values. Ki values are calculated from IC ₅₀ values using the Cheng-Prusoff (1973) relationship.

1.2 Results The results shown in FIGS. 1 (A) and (B) show that trimebutine, its stereoisomers and their metabolites [ ³ H] from their binding sites on rat cortical synaptosomes.
] -Showing that it replaces batrachotoxin with potency between that of bupivacaine (Ki = 7.14 ± 0.96) and that of fluralidin (Ki = 0.38 ± 0.05 μM). There is. For all of the compounds, the [ ³ H] -batracotoxin substitution was complete and the calculated Hill coefficient was close to 1 (FIG. 1). The affinity of trimebutin is found to be Ki = 2.66 ± 0.15 μM. In the case of this compound, the corresponding stereoisomers showed the same affinity as the racemates, indicating that there was no stereoselectivity. (S) enantiomer and (R)
The numerical values relating to the enantiomers are Ki = 3.31 ± 0.36 μM and Ki = 2.89 ± 0.88 μM, respectively.

In the case of Nor-TMB, the numerical values relating to the (S) enantiomer and the (R) enantiomer are Ki = 0.80 ± 0.04 μM and Ki = 1.26 ± 0, respectively.
． It is 07 μM. Thus, this example shows that trimebutine, Nor-TMB and their corresponding stereoisomers are comparable to the [ ³ H] -batracotoxin binding site compared to the two sodium channel blockers bupivacaine or flunarizine. It has an affinity of the size of.

Example 2 [ ³ H] -Glutamate Release The purpose of this example is to evaluate the ability of trimebutine and its metabolites to inhibit glutamate release from rat spinal cord slices. This example shows that trimebutine, its metabolites and their corresponding stereoisomers inhibit veratridine-induced glutamate release in vitro. Veratridine is a voltage-dependent Na ⁺
It is known that activating channels triggers glutamate release, resulting in Na ⁺ influx with a continuous decrease in transmembrane gradient (We.
rmelskirchen et al., 1992).

2.1 Materials and Methods a) Buffers Two buffers are prepared: formulation buffer [denatured Krebs solution:
119 mM NaCl, 5 mM KCl, 0.75 mM CaCl ₂ , 1.2 m
M MgSO ₄ , 1 mM NaH ₂ PO ₄ , 25 mM HEPES, 1 mM Na
HCO ₃ , 11 mM D-glucose, 67 μM EDTA, 1.1 mM L-
Ascorbic acid (pH 7.4) gassed with 95% O ₂ and 5% CO ₂ ] and E
A superfusion buffer that is the same as the formulation buffer except that DTA and ascorbic acid are omitted. The test compound and veratridine are diluted with this supercooling buffer.

[0070]   b) Rat spine section   The animal was decapitated, and a lumbar spinal section 1.5 cm was isolated after lumbosacral laminectomy, and 95% O ₂ And 5% CO₂Immerse in gas-treated ice-cold modified Krebs solution. Remove the dura
All root roots and dorsal roots.
roots) at the root of the entrance zone. McKill Wayne (McIll
wain) Slice using 3 consecutive sections performed using a tissue chopper
Prepare (cubic-like blocks 250 μm thick).

C) Super-melting test Maintained under oxygenation conditions, 10 μM L-glutamic acid and 4 μCi
Slices are incubated for 5 minutes at 30 ° C. in 5 ml of formulation buffer containing / ml [ ³ H] -glutamic acid. After incubation, these slices are transferred to the superthaw chamber in an automatic superthaw (Brandel). This device uses Apple I in a series of buffers used to perform 20 tests simultaneously and to melt.
Ie (Apple IIe) Consists of 20 chamber devices that allow control by computer programming. This system allows testing of different test groups in the same run (5 chambers 4 groups). After washing for 45 minutes at a flow rate of 0.5 ml / min, veratridine (40 μM) is added to the superfusion medium over 5 minutes.

When the drugs are tested (trimebutine and its stereoisomers), they are added to the superfusion medium at 15 minutes before and also during the addition of veratridine. The supermelt fraction corresponding to 5 minutes is collected over 30 minutes following this stimulation. At the end of this run, remove the slices from the thaw chamber and remove the scintillation fluid (
2.5 ml of Hionic Fluor, Packard) is added to the slices and each fraction. Liquid scintillation spectrophotometer (Minaxi, Pac
card) is used to measure radioactivity. Radioactive efflux is mainly due to [ ³ H
] -Presumed to be due to glutamate efflux (Turner and Dunlap)
, 1989).

D) Data Analysis All numbers are expressed as the mean ± SEM of at least 5 measurements. The radioactivity release associated with each fraction is represented by the fraction release calculated by dividing the radioactivity of each fraction by the amount remaining on the filter. The stimulation produced by veratridine is quantified by accumulating the release of radioactivity measured in the fractions collected after stimulation. The effect of the test compound is evaluated as a percentage of inhibition by comparing the total amount of radioactivity released in the control chamber with the total amount of radioactivity released in the chamber that was superfused with the test compound. From these percent inhibition, it is calculated by plotting the inhibition probit value versus the concentration log value on a graph. Statistical analysis is performed using Student's unpaired two-tailed t-test. Statistical deviations are considered significant at P <0.05.

2.2 Results The results shown in Figure 2 show that trimebutine dose-dependently inhibits veratridine-induced glutamate release at concentrations higher than 60 μM (Figure 2A). Furthermore, at concentrations as high as 100 μM, 50-60% inhibition can be achieved. (R) -Trimebutine exhibits a similar appearance to the racemate, while
(S) -Trimebutine showed significant inhibition from 3 μM concentration (FIG. 2A). Estimated I
The C ₅₀ is 15.2 μM for (S) -trimebutin, but could not be calculated for trimebutine and (R) -trimebutin (IC ₅₀ > 100 μM). N
In the case of or-TMB and its stereoisomer (Fig. 2B), this inhibitory effect was 3 μM,
Significant at 10 μM and 30 μM (p <0.01) and IC ₅₀ values of 8.4 μM
It was M.

(S) -Nor-TMB has a similar activity to the racemate (IC ₅₀ = 6.3 μM).
And the numerical value of the second enantiomer (R) -Nor-TMB (IC ₅₀ = 16.
3 μM). These results are consistent with the results from another publication that reports that compounds that inactivate voltage-gated Na ⁺ channels prevent veratridine-induced glutamate release in vitro and in vivo (Lees and Leach, 1993). In a similar manner, the effect of TMB and related compounds on veratridine-induced glutamate release is due to their blocking activity on sodium channels.

[0076]   When bupivacaine is evaluated under the same test conditions (FIG. 2C), IC of 8.2 μM ₅₀ The value can be estimated.   Morphine is found to be inactive in this paradigm up to 100 μM (FIG. 2).
C). The lack of morphine effect in this model is due to the glutamate of trimebutine.
Opioid properties (Roma)
n et al., 1987).

These results importantly demonstrate that trimebutine exhibits higher activity than bupivacaine. This example is of great importance in showing the important role of glutamate and excitatory amino acids (EAA) in the transmission of nociceptive messages and more specifically in the hyperalgesic state. In this regard, the discovery that TMB and its metabolites can reduce extracellular levels of glutamate by inhibiting glutamate release from presynaptic spools reveals an interesting property of TMB in therapeutic applications as an analgesic. ing.

Example 3: Electrophysiological Testing The purpose of this example is to test the effect of trimebutine and its stereoisomers on sodium current. 3.1 Materials and Methods a) DRG Neurons Tests for sodium current are performed using cultured rat dorsal root nerve muscle (DRG) excised from 14-15 day old rat embryos. Cell isolation and culture is performed by Valm
Derived from the method disclosed by Ier et al. (1989). Pregnant and has Sprague - an Dawley rats killed by placing 5-6 minutes CO ₂ atmosphere.

Three to five embryos were harvested by aspiration and then antibiotics (streptomycin, 5
0 μg / ml; penicillin, 50 U / ml) in Petri dishes containing B medium below. This B medium contained the following components (μM): 137 N
aCl, 5.4 KCl, 0.4 Na ₂ HPO ₄ , 0.8 MgSO ₄ , 0.8
MgCl _2, 1.8 CaCl _2, 6 glucose, 10 HEPES. The dorsal root ganglia are removed from the dissected spine and then digested in 2 ml of Dulbecco's modified Eagle's medium containing 0.1% trypsin for 6 minutes. The cells were mechanically dissociated with a flame-polished Pasteur pipette, and polyornithine-laminin (
Plate forming with polyornithine-laminine) coated dishes.
This culture medium is Neurobasal medium containing 0.5 mM glutamine and 25 μM glutamate. Cells are incubated at 37 ° C. in 5% CO ₂ . The electrophysiological test is performed 4 to after plate formation.
Do at 6 to 24 hours.

B) Electrophysiology Conventional whole cell patch clamp tests are performed at room temperature using an HPC7 (List) patch clamp amplifier. D
RG neurons were transformed into 143 NaCl; 10 CaCl ₂ ; 5.6 KCl; 2
MgCl ₂ ; containing 5 glucose and 10 HEPES, pH of NaOH
Hanks induction medium (osmotic pressure: 300 to 3) adjusted to 7.4 by
Immerse in 10 mosm / l). To record sodium currents, calcium is replaced by Mg ²⁺ in the presence of 10 mM TEA (tetraethylammonium). A patch-type electrode used for current recording is filled with the following salt solution (by mM): 140 CaCl, 1.1 EGTA (ethylene glycol-bis (β-aminoethyl ether) N, N, N ′, N′-4 Acetic acid), 5 HEPES, 2 M
gCl ₂ . pH is adjusted to 7.2-7.3 with CsOH (osmotic pressure: 290 m
osm / l).

These electrodes are connected to a P87 puller (Sutter Instr).
1.5 mM glass capillary (GC150TF, Clar)
k Electromedical Instruments) in four stages and flame abraded. Tip resistance is 2-3M
Ω. The drug was dissolved in a bath medium (stock solution at 10 ^-2 M in DMSO (dimethylsulfoxide)) and a glass pipette (50-60 μM located from the recorded cells).
(Pneumatic Pico)
pump PV820, WPI).

C) Calculations Data are collected at 2 kHz. Build the software for stimulation, acquisition and analysis yourself. Dose-response curves are generated using various drug concentrations spaced by the wash period. Each point is the average of 3 to 6 tests ± SEM. Minimum squared test (Minsq) program: y = 1 / (1+ [X] ⁿ /
IC ₅₀ ⁿ ), where y is the fraction of Na ⁺ current that persists in the presence of drug applied at concentration [X], IC ₅₀ is the concentration of drug that half blocks Na ⁺ current, and n is the Hill coefficient corresponding to the number of drugs required to block one Na ⁺ channel), and is fitted to a theoretical Hill curve.

3.2 Results FIG. 3A shows that 0.1 of trimebutine on sodium current in DRG neurons.
The effect of sequential 20 second application at μM and 1 μM is shown. In this representative test, TMB induced a reversible block of current corresponding to 13% and 61% at 0.1 and 1 μM, respectively. This blockage occurred without evidence of any changes in current movement (FIG. 3B) and voltage dependence (FIG. 3C). 0.01, 0
． The dose-response curves obtained by applying 1, 1 and 10 μM trimebutine are shown in FIG. 3 (D) as a plot of the current fraction remaining in the presence of blockers.
Is shown in.

[0084]   The inhibition parameters calculated from this curve are IC₅₀= 1.05 ± 0.09 and
And n_H= 1.09 ± 0.10. Parameters calculated for Nor-TMB
The motors are very similar.   Kinematic tests are performed with (R, S) -TMB. Non-blocking rate k_offIs shielded
Time constant τ for exponential recovery from failure_off= 34 ± 4 seconds (n = 6)
Ru: k_off= 1 / τ_off= 29 10^-3s^-1.   Cutoff rate k_onIs K_D= K_off/ K_onEstimated from: k_on= 35-40 10^-3s ^-1 μM^-1. These reaction rates are⁺Three drugs as channel blockers
For example, 10 μM (R, S) -TMB has a time constant of 2.2 seconds.
Shut off the channel.

These electrophysiological data demonstrate that TMB, its stereoisomers and its metabolites reversibly block sodium currents in DRG neurons with an IC ₅₀ of about 1 μM [ ³ H]. -Batrachotoxin binding (Example 1)
And confirm the results of glutamate release (Example 2). Since the Hill coefficient is about 1, this blockage follows a simple bimolecular reaction, ie one molecule of blocker is Na ⁺
It appears to occur by interacting with a site on the channel. Therefore,
The IC ₅₀ value is a measure of the dissociation constant K _D of the blocker.

Thus, the effect of trimebutine and its related compounds on Na ⁺ current, which appears to have an inhibitory effect on glutamate release, indicates a potent therapeutic effect of these compounds on pain. Sodium channel blockers, such as local anesthetics, are known to block the generation and transmission of nerve impulses by inhibiting the current through voltage-gated Na ⁺ channels in the nerve cell-membrane (Strichartz and Rit.
chie, 1987). The effect of TMB and related compounds on the Na ⁺ current, which is probably responsible for the inhibitory effect on glutamate release, indicates a strong therapeutic effect of these compounds on pain.

Example 4: Corneal Reflex Test in Rabbit The purpose of this example is to demonstrate the anesthetic properties of trimebutine or its stereoisomer in comparison to a control local anesthetic such as lidocaine. 4.1 Materials and Methods a) Animals: Male White New Zealand Rabbits (CEGAV, L) weighing 1.9-2.7 kg.
es Hauts Noes, Saint Mars d'Egren, F
race) was used. The animals are 45% to 65% relative humidity and 7.30 am
Individually housed in a cage placed in an animal room with an air conditioner (17-21 ° C) maintained on an artificial day / night cycle with lights on.

B) Corneal Reflex Test The test substance is administered as a solution in sterile water (Baxter, Maurepas, France). The test substance concentration is expressed as a percentage (weight / volume) of active compound (base form). Each test compound at each concentration is tested in 2 eyes of 5 animals (ie 10 measurements / substance and / concentration). On the test day, animals are placed in restraint cages in a quiet room. After 20-30 minutes, the first measurement of corneal sensitivity is made. Any animals showing partial or complete corneal insensitivity or eye damage prior to dosing are excluded from the study. Immediately after the first measurement, test substances or their vehicle 2 × 50 μl are applied to the cornea. Two drops are applied to each eye at 1 minute intervals. Corneal sensitivity is subsequently measured at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes and 60 minutes after infusion, then 2 hours, 3 hours and 4 hours after infusion. Measure at the time of. Corneal sensitivity is measured by gently touching the center of the cornea with a looped nylon thread (0.3 mm diameter). This operation is repeated at regular 2 second intervals for each measurement. The number of stimuli that produce corneal reflexes is recorded for each test and each eye.

C) Data analysis results are expressed as percentage inhibition of corneal reflexes calculated for each set of 10 stimuli:% corneal reflex inhibition = 10− (number of stimuli evoking corneal reflexes) × 10 in each test group. For, determine the median value. The effect of the test compound is compared with the value of the vehicle using the Mann-Withney non-parametric U test at each measurement time point. The area under the curve is taken as the first 6 post-drip for each animal and each concentration.
Calculated by the trapezoidal method of Bourget et al. (1993) over 0 minutes. TM
The relative potency of B is compared to the lidocaine hydrochloride value from each mean area under the curve using the analysis of covariance method.

4.2 Results TMB produced dose-dependent local anesthesia on the rabbit cornea (FIG. 4A).
. The first significant effect was obtained with a 0.1% concentration and lasted for 20 minutes. Instillation of 0.3% or 0.1% TMB resulted in complete local anesthesia lasting over 60 minutes. Under the same conditions, lidocaine (FIG. 4B) was found to be inactive up to a concentration of 0.3%. At 6% concentration, the local anesthetic effect was complete only during the 25 minute period, but no further inhibition of corneal reflexes was seen at 60 minutes after instillation. When comparing the areas under the curves, it was calculated that TMB was 17 times more potent than lidocaine.

[0091]Example 5: PGE₂-Induced hyperalgesia   The purpose of this study was to test TMB in combination with an opioid analgesic, its stereoisomerism.
The antihyperalgesic activity of the body and its metabolites was determined in rats by prostaglandin E ₂ (PGE₂) To evaluate induced hyperalgesia.   a) animals   Tested with Sprague-Dawley rat neonates (100-120 g)
I do. Place 5 of these animals in a cage and place them under the 12/12 day / night cycle.
Adapt to animal room conditions for 5 days at a constant room temperature of 22 ° C. Free feed and water
Give to.

B) Test A solution of PGE ₂ (1 mg / ml) was added to 10% (v
/ V) Prepare as a raw material solution in alcohol and store at 4 ° C for 4 days. A solution of PGE ₂ (1 μg / ml) is freshly prepared twice a day in sterile saline and 100 μl is injected into the left foot of the rat twice daily under the foot for 4 days. Using this method, hyperalgesia is present for at least 1 week after completion of 4 days of treatment. Control animals (saline or natural group) receive sterile saline instead of PGE ₂ under the same test conditions.

Hyperalgesia is assessed by the Randall and Selitt test (Randall and Setill).
o, 1957) by analgesimeter (Ugo Ba
sile). This analgesimeter is basically a device that exerts a force that increases at a constant rate. This force is applied to the paw of an animal placed on a small pedestal under a conical pressure tool. When the operator steps on the pedal switch, a mechanism for exerting that force is started. Nociception threshold (threshold recorded in Figures 5 and 6)
Is defined as the force (expressed in grams) that a rat takes to withdraw its paw. This threshold is measured before and after treatment.

Drugs (trimebutin and / or morphine) are given by the subcutaneous route 30 minutes before the second measurement after treatment. Control animals (saline or natural and PGE ₂ treated groups) are given the corresponding vehicle without drug (trimebutine and / or morphine) under the same test conditions. The natural group is referred to as a natural / vehicle group in the following c), and is equivalent to a group of animals given a saline solution instead of PGE ₂ and given a vehicle containing no drug (one or more kinds). To do.

The PGE ₂ treatment group is referred to as the PGE ₂ / vehicle group in c) below and corresponds to the group of animals receiving PGE ₂ and receiving no vehicle (one or more). To do. In the first treatment (designated T1 in FIG. 5), morphine is administered alone at a dose of 0.3 mg / kg. In the second treatment (designated T2 in FIG. 5), trimebutin was 100 mg / kg.
Administered alone. In the third treatment (designated T3 in FIG. 5), morphine is administered at a dose of 0.3 mg / kg with trimebutine administered at a dose of 100 mg / kg. In another test result, shown in Figure 6, animals are treated with different doses of morphine alone to assess the potentiation and / or synergistic effect of trimebutine on morphine.

C) Data Analysis Data are shown as mean ± SEM. Statistical significance levels were measured for a pair of samples by the Student's t-test (Tallarrida and Murray, 1987) and differences of p <0.05 are considered statistically significant. Percent antinociception or analgesic activity is calculated according to the following formula:

D) Results The results of the above tests are shown graphically in FIG. 5 and summarized in the table below. The percentage of analgesic activity is calculated as described in c) above.

The antinociceptive activity of the morphine / trimebutin combination is not statistically different from the antinociceptive activity obtained with morphine at 10-fold or higher doses (morphine 0.
3 mg / kg + trimebutine = morphine 3 mg / kg; FIG. 6). These results show the particular advantage of the combination for reducing the secondary effects of morphine (tolerance, dependence, constipation and hypopnea) and maintaining a significant analgesic effect.

These results show a synergistic enhancement of the analgesic effect of morphine with trimebutine and a synergistic enhancement of the analgesic effect of trimebutine with morphine. Furthermore,
These results show the synergistic effect of trimebutine on morphine and the synergistic effect of morphine on trimebutine. In fact, the addition of trimebutine to a specific dose of morphine increases the antinociceptive activity 3-fold compared to the antinociceptive activity obtained by morphine used alone at the same dose. Addition of morphine to a specific dose of trimebutine increases antinociceptive activity by a factor of 2 compared to the antinociceptive activity obtained with trimebutine used alone at the same dose.

Example 6 Rat Mononeuropathy The purpose of this study is to evaluate TMB, its stereoisomers and its metabolites in combination with opioid analgesics in a rat neuropathy model. Study of Pain (IASP) Ethical Guideline
Commitment to es (examination of pain ethics guidelines)
search and Ethical Issues of the Inte
national Association has been adhered to in these trials. In particular, the duration of the study is kept as short as possible and the animal number is kept to a minimum.

A) Animals: Male Sprague-Dawley rats (C newborn weighing 175-200 g) (C
harles River, France, species name: Crl: CD (SD) BR)
, N = 45 is used. The rats are housed in the test facility for one week before the test. These rats were maintained on a 12-hour day / night cycle and received standard laboratory chow and tap water ad libitum at room temperature of 20-22 ° C.

B) Surgery: On the right hind limb, Bennett and Xie (1988) and Attal et al., 199.
According to the method disclosed by No. 0, unilateral peripheral mononeuropathy is generated.
Rats receive sodium pentobarbitone [Nembutal, 50
mg / kg, i. p. ] To anesthetize. The common sciatic nerve is exposed by blunt dissection in the mid thigh; 4 ligatures (5-0 chrome gut, approximately 1 mm apart) are placed around the nerve.

C) Antinociception Test: The test is performed in a quiet room. Animals are not previously adapted to the test situation. The tester is blinded to the drug and dose used. Each animal receives the drug only once and is used for only one study. The antinociceptive effect is Ugo Basile (
(Commerio, Italy) Analgesia and vocal thresholds evoked by applying pressure to both the nerve-injured hindlimb and the contralateral hindlimb.
It is measured by the ization threshold). This device produces a linearly increasing mechanical force applied by a dome-shaped plastic tip (diameter = 1 mm) on the back of the limb. The tip is placed between the third metatarsal and the fourth metatarsal (in the sciatic nerve area) and then force is applied until the rat shouts. For each rat, the control threshold (mean of two consecutive stability thresholds expressed in g) is measured before drug infusion. The vocalization threshold is then measured every 10 minutes until it returns to the level of the control value.

D) Data analysis Data are the mean ± S. E. M. Express as. The area under the curve (AUC) is
Calculate using the trapezoidal method. The statistical significance of this data was determined by one-way deviation analysis (A
Analyze by NOVA). The significance found was then followed by Tukey.
) Test. Simple regression (linear model) is performed to establish dose-dependent effects. Statistical analysis is based on a statistical computer program (Statgr
aplus Plus, Diagnostic, Rockville, MD)
Using. P <0.05 is used as the standard for statistical significance.

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[Brief description of drawings]

FIG. 1: [ ³ H] -batracotoxin (batr) binding to rat cortical synaptosomes.
2 shows the effect of TMB (A), Nor-TMB (B) and their corresponding stereoisomers on achotoxin).

FIG. 2. TM for veratridine-induced glutamate release from rat spinal cord slices.
Shows the effect of B (A), Nor-TMB (B) and their corresponding stereoisomers. Morphine and bupivacaine (C) were tested under the same conditions.

[Figure 3]   Figure 7 shows the effect of TMB on sodium current measured in DRG neurons.

FIG. 4 shows the local anesthetic effect of TMB (A) and lidocaine (B) measured by rabbit corneal reflex.

FIG. 5 shows the percentage of analgesic activity before and after treatment in native, control and morphine and / or trimebutine treated groups.

FIG. 6 shows the percentage of analgesic activity before and after treatment in natural, control and morphine and / or trimebutine treated groups.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/485 A61K 31/485 45/00 45/00 A61P 23/00 A61P 23/00 23/02 23 / 02 25/04 25/04 43/00 121 43/00 121 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, A , AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN , MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Roman, Francois France Vitry-Sull-Seine, Alepierre Fresnay, 11F term (reference) 4C084 AA19 MA02 NA05 NA06 ZA041 ZA081 ZA211 ZC751 4C086 AA01 AA23 BC02 MA04 BC27 BC27 BC04 NA05 NA06 ZA04 ZA08 ZA21 ZC75 4C 206 AA01 AA02 DB17 DB54 FA02 FA10 MA02 MA04 NA05 NA06 ZA04 ZA08 ZA21 ZC75

Claims (29)

[Claims] 1. Trimebutine [2-dimethylamino-2-phenylbutyl-
3,4,5-Trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one corresponding stereoisomer thereof and an opioid analgesic. 2. The product according to claim 1, wherein the compounds can be used simultaneously, separately or sequentially for the treatment and / or prevention of pain and / or nociception. 3. An opioid analgesic is morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol.
nol), onyx morphone, alfentanyl, buprenorphine
, Butorphanol, fentanyl
yl), sulfentanyl, meperidine (mepe)
ridine), methadone, nalbuphine
fine), propoxyphene and pentazocine or their acceptable salts,
A product according to any one of claims 1, 17 or 25. 4. The product according to claim 3 or 17, wherein the opioid analgesic is morphine or an acceptable salt thereof. 5. Trimebutine [2-dimethylamino-2-phenylbutyl-]
3,4,5-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomer and an opioid analgesic together with at least one pharmaceutical carrier or excipient. 6. Trimebutine [2-dimethylamino-2-phenylbutyl-
3,4,5-Trimethoxy-benzoate hydrogen maleate] or its corresponding stereoisomers and opioid analgesics for the preparation of a medicament for the prevention and / or treatment of pain and / or nociception. 7. Use according to claim 6 for simultaneous, separate or sequential administration in the treatment and / or prevention of pain and / or nociception. 8. Use according to claim 6 for the preparation of a medicament for the prevention and / or treatment of acute pain. 9. Use according to claim 6 for the preparation of a medicament for the prevention and / or treatment of inflammatory pain. 10. For the preparation of a medicament for the prevention and / or treatment of chronic pain,
Use according to claim 6. 11. Trimebutin 50 to 900 mg / day, preferably 300
Use according to any of claims 6, 18-22, 26 and 27, administered at a dose of ~ 600 mg / day. 12. Use according to any of claims 6, 18-22, 26 and 27, wherein the opioid analgesic is administered at a dose of 0.01-250 mg / day, depending on the opioid analgesic selected. . 13. Use according to any of claims 6, 18-22, 26 and 27, wherein morphine is administered at a dose of 2-220 mg / day. 14. A method of preventing and / or treating pain and / or nociception, which method comprises administering a trimebutine and an opioid analgesic to a patient in need thereof. 15. The method of claim 14, wherein the administration of trimebutine and the opioid analgesic is simultaneous, separate or sequential. 16. A method for preparing a pharmaceutical composition containing trimebutine or a stereoisomer thereof and an opioid analgesic, which comprises combining the trimebutine and opioid analgesic with a pharmaceutically acceptable carrier or excipient. The above-mentioned preparation method comprising. 17. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyltrimebutine, at least one metabolite thereof or at least one metabolite. Combinations of their corresponding stereoisomers and opioid analgesics for the treatment or prevention of pain, or for anesthesia, for simultaneous, separate, sequential, or dispersed over a period of time. Products included as a combined product. 18. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one metabolite. Use of their corresponding stereoisomers and opioid analgesics as a medicament. 19. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one metabolite. Use of their corresponding stereoisomers and opioid analgesics for the treatment or prevention of pain. 20. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, for reducing or suppressing the dose of an opioid analgesic, at least 1
Use of certain of their metabolites or at least one of their corresponding stereoisomers in combination with opioid analgesics. 21. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N- for reducing or suppressing at least one side effect or disadvantage of an opioid analgesic. Use of desmethyl trimebutine, at least one of their metabolites or at least one of their corresponding stereoisomer in combination with an opioid analgesic. 22. The at least one side effect or disadvantage is selected from the list including sedation, respiratory depression, decreased gastrointestinal motility, constipation, nausea, tolerance, dependence, toxicity or vomiting. Use as described in. 23. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], N-desmethyl trimebutine, at least one metabolite thereof or at least one metabolite. A method for the prevention and / or treatment of pain, comprising administering the corresponding stereoisomer and opioid analgesic to a patient in need thereof. 24. Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate], at least one metabolite thereof or at least one corresponding stereoisomer thereof. 24. The method of claim 23, wherein the and the opioid analgesic are administered simultaneously, separately or sequentially. 25. Pain is pain associated with nociception and / or hyperalgesia and / or allodynia and / or central hypersensitivity and / or somatic pain and / or visceral pain and / or acute pain and / or Or chronic pain and / or post-operative pain and / or headache and / or inflammatory pain and / or neurological pain and / or muscle-skeletal pain and / or cancer-related pain and / or vascular pain The product according to claim 2 or 17, characterized in that: 26. Pain relates to nociception and / or hyperalgesia and / or allodynia and / or hypersensitivity and / or somatic pain and / or visceral pain and / or acute pain and / or Or chronic pain and / or post-operative pain and / or headache and / or inflammatory pain and / or neurological pain and / or muscle-skeletal pain and / or cancer-related pain and / or vascular pain 20. Use according to any of claims 6, 7 and 19. 27. The opioid analgesic is morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol.
anol, onyxmorphone, alfentanyl, buprenorphine
), Butorphanol, fentanyl
nyl), sulfentanyl, meperidine (mep)
eridine), methadone, nalbuphine (nalb)
27. Use according to any of claims 17 to 22 and 26, selected from among: upine), propoxyphene and pentazocine or their acceptable salts. 28. The opioid analgesic agent is morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol.
anol, onyxmorphone, alfentanyl, buprenorphine
), Butorphanol, fentanyl
nyl), sulfentanyl, meperidine (mep)
eridine), methadone, nalbuphine (nalb)
25. The method according to any of claims 14, 15, 23 and 24, which is selected from among: upine), propoxyphene and pentazocine or their acceptable salts. 29. The product of claim 17, wherein the anesthesia is local or general anesthesia.